The present invention relates to the use of xenon for treating or preventing hypersensitivity to pain and, consequently, pain chronisication.
It is known that, following an inflammation or tissue or nerve damage, a process of pain sensitization will develop and result in hypersensitivity to pain. This is reflected by the appearance of hyperalgesia, i.e. an exaggerated response to a nociceptive stimulation, and/or of allodynia, i.e. a painful sensation brought about by a non-nociceptive stimulus, and persistent pain, as recalled by the articles by C. Woolf et al, Neuronal plasticity: increasing the gain in pain, Science, 288, 1765-9 (2000); J. Scholz et al, Can we conquer pain ?, Nat Neurosci. 5 Suppl, 1062-7 (2002); and O. Wilder-Smith et al, Postoperative hyperalgesia: its clinical importance and relevance, Anesthes., 104, 601-7 (2006).
In the central nervous system (CNS), several experimental and clinical studies have shown an essential role for excitatory amino acids in sensitization to post-traumatic pain via N-methyl-D-aspartate (NMDA) receptors, as recalled by the review B. Chizh et al., NMDA antagonists and neuropathic pain-Multiple drug targets and multiple uses, Current Pharmaceutical Design, 11, 2977-94 (2005).
The phenomenon of pain sensitization subsequent to an inflammation or tissue or nerve damage, expressed as hyperalgesia or allodynia and increased pain, is now considered to be the key mechanism responsible for the development of post-operative and chronic pain, as recalled by F. Perkins et al, Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology 93, 1123-33 (2000); or by W. Macrae, Chronic pain after surgery. British Journal of Anaesthesiology, 87, 88-98 (2001).
In particular, during general anesthetics, it is customary to administer volatile or intravenous hypnotics to patients, or intravenous analgesic or opioid substances. Mention may in particular be made of the following anesthetic products which are commonly used in anesthesia, such as fentanyl, alfentanyl, sufentanyl, remifentamil or other opioids, etc.
However, it has been noted that these volatile or intravenous opioids induce and/or amplify post-operative hyperalgesia, which is reflected by sensitivity to pain in patients which is of increased intensity after the operation. It has, moreover, been shown that this opioid-induced greater sensitivity to pain is linked to hyperactivity of the NMDA receptor, as recalled by the articles by Simonnet et al., Opioid-induced Hyperalgesia: abnormal or normal pain ? Neuroreport, 14, 1-7, (2003); et Angst et al., Opioid-induced Hyperalgesia, Anesthesiology, 104:570-87. (2006).
This effect is notable for a long period, which can in particular be up to 1 year, and therefore results in a decrease in the quality of life of the patients since they will be more sensitive to pain during this time.
In order to attempt to remedy this, document FR-A-2914633 has proposed the use of a gas mixture containing oxygen (O2) and from 2 to 10% by volume of xenon (Xe) for preventing or minimizing post-operative hyperalgesia in humans.
Indeed, xenon, which is an NMDA receptor antagonist, as taught by N. Franks et al, How does xenon produce anaesthesia ? Nature, 396, 324. (1998), has an acute analgesic effect, as recalled by D. Ma et al., Xenon exerts age-independent antinociception in Fischer rats, Anesthesiology. 100, 1313-8. (2004), and S. Petersen-Felix et al, Comparison of the analgesic potency of xenon and nitrous oxide in humans evaluated by experimental pain; Br J Anaesth. 81, 742-7 (1998).
From there, given that NMDA receptors have a major essential role in pain sensitization induced by trauma and amplified by opioids, this property can be used to prevent or treat hypersensitivity to pain, by virtue of the NMDA receptor antagonist properties of xenon used as a pharmacological agent.
However, the solution proposed by FR-A-2914633 is not ideal since the xenon concentrations are too low and do not therefore make it possible to obtain a really effective treatment for preventing or treating hypersensitivity to pain.
Moreover, document WO-A-02/22141 teaches the use of xenon as a cardiovascular protective agent, sedative, analgesic, etc.
In addition, D. Ma et al, Xenon exerts age-independent antinociception in Fisher rats, May 2004, Anesth., vol. 100, no 5, pages 1313-1318, show that the analgesic action of xenon is independent of the age of the patients, including in the fetus or the newborn, whereas S. Pertersen-Felix et al, Comparison of the analgesic potency of xenon and nitrous oxide in humans evaluated by experimental pain, November 1998, Brit. J. of Anesth., vol. 81, no 5, p. 742-747, compare the analgesic effects of xenon with those of N2O.